C-terminal Src kinase controls development and maintenance of mouse squamous epithelia

• Published in: The EMBO journal Vol. 26; no. 5; pp. 1234 - 1244
• Main Authors: Yagi, Reiko, Waguri, Satoshi, Sumikawa, Yasuyuki, Nada, Shigeyuki, Oneyama, Chitose, Itami, Satoshi, Schmedt, Christian, Uchiyama, Yasuo, Okada, Masato
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 07.03.2007; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Cell Adhesion; Cell adhesion & migration; Cells, Cultured; Csk; Cytoskeleton - metabolism; Esophagus - cytology; Esophagus - metabolism; Gene expression; Histology; hyperplasia; Immunoblotting; Immunohistochemistry; Immunosuppressive Agents - pharmacology; Inflammation - metabolism; Inflammation - pathology; K5 promoter; Keratin-5 - genetics; Keratin-5 - metabolism; Keratinocytes - cytology; Keratinocytes - metabolism; Kinases; Matrix Metalloproteinases - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Microscopy, Electron, Transmission; Mutation; Phenotype; Prenatal development; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Rodents; Signal transduction; Signal Transduction - drug effects; Skin - cytology; Skin - metabolism; Skin - ultrastructure; squamous epithelia; Src family kinase; src-Family Kinases - genetics; src-Family Kinases - metabolism; Tacrolimus - pharmacology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7601595

Carboxy‐terminal Src kinase (Csk) is a negative regulator of Src family kinases, which play pivotal roles in controlling cell adhesion, migration, and cancer progression. To elucidate the in vivo role of Csk in epithelial tissues, we conditionally inactivated Csk in squamous epithelia using the keratin‐5 promoter/Cre‐loxP system in mice. The mutant mice developed apparent defects in the skin, esophagus, and forestomach, with concomitant hyperplasia and chronic inflammation. Histology of the mutant epidermis revealed impaired cell–cell adhesion in basal cell layers. Analysis of primary keratinocytes showed that the defective cell–cell adhesion was caused by cytoskeletal remodeling via activation of the Rac1 pathway. Mutant keratinocytes also showed elevated expression of mesenchymal proteins, matrix metalloproteinases (MMPs), and the proinflammatory cytokine TNF‐α. Inhibition of the expression of TNF‐α and MMP9 by the anti‐inflammatory reagent FK506 could cure the epidermal hyperplasia, suggesting a causal link between inflammation and epidermal hyperplasia. These observations demonstrate that the Src/Csk circuit plays crucial roles in development and maintenance of epithelia by controlling cytoskeletal organization as well as phenotypic conversion linked to inflammatory events.